By using m-chlorophenylpiperazine (m-CCP, a 5-HT1 agonist) as a challenge agent, we have demonstrated that long-term (21-25 days) lithium (antidepressant/antimanic) treatment accentuated m-CPP's effect on plasma prolactin and corticosterone but not on growth hormone levels. On the other hand, short-term (2-6 days) lithium treatment accentuated m-CPP's effect on plasma corticosterone but not on plasma prolactin or growth hormone levels. In another study, long-term (21 days) treatment with imipramine, clomipramine (tricyclic antidepressants) and clorgyline (monoamine oxidase type A inhibiting antidepressant) produced significant decreases in plasma corticosterone levels in Fawn-Hooded (FH) rats. On the other hand, plasma adrenocorticotropic hormone (ACTH) levels were not altered by chronic imipramine or clorgyline treatment but were significantly higher in chronic clomipramine-treated FH rats. These findings demonstrate a differential effect of chronic antidepressant treatment on plasma ACTH and corticosterone concentrations in FH rats and, furthermore, support our earlier studies suggesting that the FH rat strain may represent a genetic model of depression. In a separate series of experiments, chronic administration of imipramine, clomipramine and fluoxetine (5-HT uptake inhibiting antidepressants) but not clorgyline (monoamine oxidase type A inhibiting antidepressant) or 5-HT receptor agonists (m_CCP, DoI, 8-OHDPAT) decreased 5-HT transport steady-state mRNA concentrations in rat brain. In another study, chronic fluoxetine treatment decreased Galphas mRNA in midbrain, while mRNA expression of the novel G protein alpha subunits, Galphaq, and Galpha12, was increased in neostriatum and frontal cortex. These findings indicate that regulation of G protein function and the 5- HT transporter by antidepressant drugs may occur at the level of gene expression and , furthermore, may contribute to the neuroadaptive mechanisms that likely underlie their therapeutic efficacy.